title: In skeletal muscle advanced glycation end products (AGEs) inhibit insulin action and induce the formation of multimolecular complexes including the receptor for AGEs.
abstract: Chronic hyperglycemia promotes insulin resistance at least in part by increasing the formation of advanced glycation end products (AGEs). We have previously shown that in L6 myotubes human glycated albumin (HGA) induces insulin resistance by activating protein kinase Calpha (PKCalpha). Here we show that HGA-induced PKCalpha activation is mediated by Src. Coprecipitation experiments showed that Src interacts with both the receptor for AGE (RAGE) and PKCalpha in HGA-treated L6 cells. A direct interaction of PKCalpha with Src and insulin receptor substrate-1 (IRS-1) has also been detected. In addition, silencing of IRS-1 expression abolished HGA-induced RAGE-PKCalpha co-precipitation. AGEs were able to induce insulin resistance also in vivo, as insulin tolerance tests revealed a significant impairment of insulin sensitivity in C57/BL6 mice fed a high AGEs diet (HAD). In tibialis muscle of HAD-fed mice, insulin-induced glucose uptake and protein kinase B phosphorylation were reduced. This was paralleled by a 2.5-fold increase in PKCalpha activity. Similarly to in vitro observations, Src phosphorylation was increased in tibialis muscle of HAD-fed mice, and co-precipitation experiments showed that Src interacts with both RAGE and PKCalpha. These results indicate that AGEs impairment of insulin action in the muscle might be mediated by the formation of a multimolecular complex including RAGE/IRS-1/Src and PKCalpha.
authors.affiliation: Dipartimento di Biologia e Patologia Cellulare e Molecolare and Istituto di Endocrinologia ed Oncologia Sperimentale del Consiglio Nazionale delle Ricerche, Università degli Studi di Napoli Federico II, Naples 80131, Italy.
authors.forename: Angela
authors.initials: A
authors.lastname: Cassese
authors.forename: Iolanda
authors.initials: I
authors.lastname: Esposito
authors.forename: Francesca
authors.initials: F
authors.lastname: Fiory
authors.forename: Alessia P M
authors.initials: AP
authors.lastname: Barbagallo
authors.forename: Flora
authors.initials: F
authors.lastname: Paturzo
authors.forename: Paola
authors.initials: P
authors.lastname: Mirra
authors.forename: Luca
authors.initials: L
authors.lastname: Ulianich
authors.forename: Ferdinando
authors.initials: F
authors.lastname: Giacco
authors.forename: Claudia
authors.initials: C
authors.lastname: Iadicicco
authors.forename: Angela
authors.initials: A
authors.lastname: Lombardi
authors.forename: Francesco
authors.initials: F
authors.lastname: Oriente
authors.forename: Emmanuel
authors.initials: E
authors.lastname: Van Obberghen
authors.forename: Francesco
authors.initials: F
authors.lastname: Beguinot
authors.forename: Pietro
authors.initials: P
authors.lastname: Formisano
authors.forename: Claudia
authors.initials: C
authors.lastname: Miele
mesh_terms: D000818:Animals; D005260:Female; D005951:Glucose Tolerance Test; D017127:Glycation End Products, Advanced / Q000378:metabolism*; D006801:Humans; D006943:Hyperglycemia / Q000473:pathology; D007328:Insulin / Q000378:metabolism*; D055504:Insulin Receptor Substrate Proteins / Q000378:metabolism; D051379:Mice; D008810:Mice, Inbred C57BL; D018482:Muscle, Skeletal / Q000378:metabolism; D051571:Protein Kinase C-alpha / Q000378:metabolism; D051057:Proto-Oncogene Proteins c-akt / Q000378:metabolism; D000067759:Receptor for Advanced Glycation End Products; D011971:Receptors, Immunologic / Q000378:metabolism; D019061:src-Family Kinases / Q000378:metabolism
chemical_list: D017127:Glycation End Products, Advanced; D007328:Insulin; D055504:Insulin Receptor Substrate Proteins; C526295:Irs1 protein, mouse; D000067759:Receptor for Advanced Glycation End Products; D011971:Receptors, Immunologic; D019061:src-Family Kinases; D051057:Proto-Oncogene Proteins c-akt; D051571:Protein Kinase C-alpha